Fat receives a lot of bad press, but patients with lipodystrophy exemplify its critical physiological importance. Lipodystrophy is characterised by the functional failure of fat, usually associated with its anatomical absence (lipoatrophy). Though a comparatively rare condition, it is relevant to many endocrinologists/ diabetologists, as it highlights the metabolic role of fat in surplus energy storage and has contributed to a deeper understanding of human insulin resistance, non-alcoholic fatty liver disease, and type 2 diabetes.

Lipodystrophies are a relatively heterogeneous group of conditions that can be broadly classified into congenital or acquired, and partial (limited to certain areas of the body) or generalised.^1,2

Congenital (generalised) lipodystrophies are the most extreme forms.³ They are autosomal recessive disorders that typically present in children who have almost no adipose tissue. In addition, there are several forms of familial partial lipodystrophy, most of which are inherited in an autosomal dominant fashion. These are often said to present around puberty, but this may be related to the fact that they become more clinically obvious in girls at this stage, as they frequently manifest as a lack of lower limb and femorogluteal fat.

Acquired partial lipodystrophy (APL) is more common, typically progresses in a cephalocaudal pattern, and is not usually associated with metabolic problems (though it can be) but it is often associated with C3 nephritic factor and glomerulonephritis. APL may occur secondary to drugs (for example, anti-retrovirals in treatment of HIV) or in association with other autoimmune disorders. Similarly, acquired generalised lipodystrophy is often associated with other autoimmune problems.

PRESENTATION OF LIPODYSTROPHY

The lack of subcutaneous fat in congenital generalised lipodystrophy is immediately obvious: patients may appear strikingly muscular and progerioid due to reduced facial fat. However, partial lipodystrophy may not be immediately apparent, and the lack of adipose may be most evident on the thighs, buttocks and upper arms.⁴ Other signs that may be found are acanthosis nigricans (refl ective of severe insulin resistance), hepatomegaly (due to hepatic steatosis) with splenomegaly (from portal hypertension) and, in some cases, pseudoacromegalic features. Women frequently present with manifestations of polycystic ovary syndrome.

Biochemically, patients have all the features of the metabolic syndrome: hyperglycaemia, dyslipidaemia and raised liver enzymes due to fatty liver. They have high insulin levels, driven by severe peripheral insulin resistance, and low leptin and adiponectin levels (variable depending on the extent of lipodystrophy), due to a lack of functional adipocytes and severe insulin resistance.

Patients with lipodystrophy often display the same metabolic features that are expected in obese people: type 2 diabetes, premature coronary artery disease, stroke and non-alcoholic fatty liver disease.

TREATMENT

Medical treatment is similar to that of obese patients with the metabolic syndrome, with dietary restriction the mainstay of treatment. Patients often require high doses of insulin (>2IU/kg per day, for example) to achieve euglycaemia. However, this can be significantly improved if leptin therapy is initiated⁵ in those with low leptin levels (a specific cut-off has yet to be agreed, but levels below 5μg/l in men and 10μg/l in women can be used as a rough guide). Leptin, whilst not yet approved in the EU, is likely to become the first-choice therapy in patients with generalised lipodystrophy, whereas its use in patients with partial lipodystrophy requires further investigation.

Bariatric surgery has also been shown to be very effective in familial partial lipodystrophy, where patients are hyperphagic and excess intake accelerates their metabolic complications. Common causes of death are cardiomyopathy, macrovascular atherosclerotic disease, and cirrhosis secondary to fatty liver.

UNDERLYING PHYSIOLOGY

Mammals have evolved to cope with sizable fluctuations in nutrient supply by storing excess energy in macromolecules. For a non-obese 70kg man, liver and muscle glycogen stores hold only about 6MJ of energy, whereas adipose tissue stores contain about 600–800 MJ as triacylglycerol (around 100-fold more than glycogen stores).

Adipocytes are ‘professional’ storage cells that contain triacylglycerol within a huge single lipid droplet. However, there is a limit to their expandability, both in terms of cellular hypertrophy and hyperplasia. Once surpassed, excess lipid accumulates in so-called ectopic sites such as the liver and muscle. These tissues are less well-adapted to cope with excess lipid, which tends to impair insulin action.⁶ This hypothesis is often referred to as the ‘adipose overflow hypothesis’.

Patients with lipodystrophy have severely limited adipose expandability; therefore this is manifest at a normal or even low body mass index. The ‘metabolically healthy’ obese continue to expand their adipose storage capacity, but if and when they reach their ‘genetically defined’ limit, they will manifest type 2 diabetes and fatty liver. It has very recently been shown that adipose expansion capacity is genetically determined, varies in adults, and is associated with dyslipidaemia and hyperinsulinaemia.⁷ Some adipose depots are of particular importance, particularly the thighs and buttocks, which is supported by evidence that a low hip circumference (separately from a high waist circumference) is a marker of metabolic risk.

LESSONS LEARNT FROM LIPODYSTROPHY

The most important principle gleaned from lipodystrophy is that weight loss is the most effective treatment for the metabolic syndrome, as it reduces the energetic load on adipocytes. This is amply demonstrated by the dramatic clinical benefits, including reversal of type 2 diabetes, associated with extreme calorie restrictive diets⁸ or bariatric surgery.⁹

It is also the mechanism underlying the action of peroxisome proliferatoractivated receptor (PPAR) agonists such as the thiazolidinediones (TZDs), which expand adipocyte storage capacity. Patients often gain weight (and fat mass) in response to TZDs, but that’s how they work. Fat should not be seen as the enemy, but increasing evidence suggests that its capacity to expand in response to sustained excess energy intake is finite and, when exceeded, serious metabolic disorder ensues.

Therefore, whilst lipodystrophy is relatively rare, it highlights the importance of ‘healthy fat’. Making the diagnosis is very useful as it may inform predictive genetic testing in families and therapeutic decisions which can be life-transforming, at least in terms of metabolic control. Many obese patients with the metabolic syndrome mimic lipodystrophy because their adipocytes are ‘full’, and the best treatment is to ‘empty’ them by weight loss.

Jake P Mann, Clinical Fellow in Paediatrics, Institute of Metabolic Science and Department of Paediatrics, University of Cambridge, UK

David B Savage, Wellcome Trust Senior Clinical Fellow, Institute of Metabolic Science, University of Cambridge, UK

REFERENCES

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